Method for preparing amines

ABSTRACT

This invention relates to the reduction of compounds containing an imminium group to an amine with an alkali metal cyanoborohydride or quaternary ammonium cyanoborohydride or the corresponding deuterium and tritium labeled materials in a solvent selected from water, tetrahydrofuran, methanol, ethanol, diethyl ether or mixtures thereof at a pH between about 2 and 12, preferably, between about 5 and 7. Compounds in which an aldehydic or ketonic functional group are to be reductively aminated are first converted to imines by an appropriate secondary or primary amine, or ammonia, which, in those cases, is included in the reaction mixture. Compounds in which the functional group to be reduced is an imine, substituted imine or imino ester are protonated by the reaction medium prior to reduction.

United States Patent [1 1 Kreevoy et a].

[ 1 Mar. 25, 1975 1 METHOD FOR PREPARING AMINES [75] Inventors: Maurice M. Kreevoy; Richard Frederic Borch, both of Minneapolis, Minn.; Jonathan Edward Colin Hutchins, Alhambra, Calif.

[73] Assignee: Regents of the University of Minnesota, Minneapolis, Minn.

22 Filed: May 22,1972

21 Appl. No.: 255,772

[52] US. Cl 260/583 R, 260/570.8, 260/571, 260/518 R, 260/570.5, 260/397.2, 260/296,

260/583 R, 260/554 E, 260/566 R, 260/563 R,

[51] Int. Cl. C076 85/08 58 Field of Search 260/583 R [56] References Cited UNITED STATES PATENTS 2,298,284 10/1942 Emerson 260/577 R 2,420,584 5/1947 Brimer et a1. 260/583 R OTHER PUBLICATIONS Abs. of Pap-Amer. Chem. Soc., 152.

Tet. Let. pp. 61-65 1960. J. Amer, Chem. Soc-July 2, 1969 3996-3397.

Primary Examiner-Elbert L. Roberts Assistant ExaminerD. R. Phillips Attorney, Agent, or Firm-Cushman, Darby & Cushman [57] ABSTRACT This invention relates to the reduction of compounds containing an imminium group to an amine with an alkali metal cyanoborohydride or quaternary ammonium cyanoborohydride or the corresponding deuterium and tritium labeled materials in a solvent selected from water, tetrahydrofuran, methanol, ethanol, diethyl ether or mixtures thereof at a pH between about 2 and 12, preferably, between about 5 and 7.

16 Claims, N0 Drawings METHOD FOR PREPARING AMINES This appeal-airs a continuation of sures-sem application Ser. No. 855,736 filed Sept. 5. 1958. now abandoned.

This invention relates to the reduction of compounds containing an imminium group to an amine by reduction with a cyanoborohydride of lithium, sodium or potassium, or a quaternary ammonium cyanoborohydride or the corresponding deuterium and tritium labeled materials.

G. Drefahl and E. Keil, J. Prakt Chem., 6,80, (1958) reported that lithium monocyanoborohydride, first prepared and described by G. Wittig, Ann. 578,209 (1951), because of its electronic structure is an outstandingly stable hydride. Drefahl and Keil report that aromatic and aliphatic carboxylic acids and esters, and azoxycompounds are not reduced by lithium monocyanoborohydrides. However, they report that aromatic and aliphatic aldehydes and alpha diketones were reduced. Their reactions were carried out in dioxane-water mixtures ranging up to pure dioxane, at reflux temperature with times up to 30 hours. This report is substantially in error, since several of the compounds reported as not reducible are actually reducible.

We have discovered that lithium, sodium and potassium cyanoborhydrides, quaternary ammonium cyanoborohydrides and the corresponding deuterium and tritium labeled materials will reduce a variety of func tional groups with remarkable selectivity. The utility of the cyanoborohydrides is enhanced by its two unique properties among hydride reducing agents: (1) the reagent is stable in acid to pH 3, and at low pH the hydro gens can be readily exchanged; (2) Because imines are partially or wholly protonated at a pH of about 7, and the reduction of the protonated imines by cyanoborohydride is very facile, while the reduction of aldehydes and ketones is very slow at this pH, at very convenient method is provided for the reductive amination of aldehydes and ltetones in yields which are near quantitative. and by prior exchange of thc hydrogcns for deuterium or tritium an efficient and economical route is available for dcutcridc or tritide reductive amination of aldehydes and kctones. The faster rate of reduction of the imminium moeity provides an excellent method for reductive amination of aldehydes and ketones under exceedingly mild conditions. The introduction of deuterium or tritium is accomplished by prior exchange of the cyanoborohydride with D or tritium labeled water at pH 3.

The method of the present invention contemplates the reduction of compounds containing an imminium group to an amine. This is accomplished by contacting at room temperature 1 mole of the compound to be reduced with an equivalent amount of one of the previously mentioned cyanoborohydrides or deuteride or tritide in a solvent selected from water, tetrahydrofuran, methanol, ethanol, diethyl ether or mixtures thereof at a pH between 2 and 12, preferably between about 5 and 7 until the imminium group is converted to an amine group. Compounds containing an imine group or an iminoester group first are converted to compounds containing an imminium group by Contact with the above acid liquor. Compounds containing an aldehyde or ketone group are first converted to the corresponding compounds containing an imminium group by contact with a liquor at a pH between 2 and 12, preferably between 7 and 9, but which also contains a nitrogen compound, such as ammonia, primary or secondary amine, and then are reduced by the 'cyanoboo ohydride to compounds containing an amine group. lf the reduction is carried out with substituted sodium pyruvate and ammonium chloride, good yields of amino acids are obtained.

The above reactions are illustrated by the following where R R and R represent H, an alkyl group,'substituted alkyl group, aryl group, substituted aryl groups, cycloalkyl groups, and cycloalkenyl groups, while R may be alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioalkyoxy, substituted thioalkoxy, thioaryloxy, or substituted thioaryloxy as well as any of the groups represented by R R and R 1. Compounds containing an imminium group.

3. Compounds containing an iminoester group.

4. Compounds containing a ketone group.

5. Compounds containing, an aldehyde group.

(3:0 llNli R-g (11-. R1;

reduction lit N amine llzi The preparation of lithium, sodim, potassium and quaternary ammonium cyanoborohydrides is described in the copending application of Robert C. Wade, Ser. No. 833,722, filed June 16, 1969 now US. Pat. No. 3,667,923 and Serial No. 833,766. filed June 16, 1969 now US. Pat. No. 3,697,232. The method comprises heating anhydrous hydrogen cyanide with an anhydrous borohydride selected from a quaternary ammonium borohydride, lithium or sodium borohydride at a temperature between about 0C. and the boiling point of the solvent in an anhydrous solvent selected from tetrahydrofuran, glyme, diglyme, triglyme, and dimethyl formamide and mixtures thereof until hydrogen ceases to be evolved and all intermediate products have been converted to the desired cyanoborohydride corresponding to the selected borohydride. The method for preparing potassium cyanoborohydride is the same except that dimethyl formamide must be used as the solvent.

As quaternary ammonium cyanoborohydrides which ,may be used, we may mention tetramethyl, tetraethyl,

tetrapropyl, tetraisopropyl, tetrabutyl, butyltrimethyl.

nyl, cetyl trimethyl and tricaprylmethyl ammonium cyanoborohydrides and their corresponding deuterides and tritium labeled hydrides.

As primary and secondary amines in the reductive amination of ketones and aldehydes we may mention.

Mono-and di-alkylamines, including isomers:

methylamine di-n-butylamine dimethylamine di-sec-but l amine ethylamine di-isobuty amine diethylamine n-amylamine sec-n-amylamine isoamylamine tert-amylamine etc.

n-propylamine isopropylamine di-( npropyl )amine di-( isopropyl) amine n-butylamine tert-butylamine Aromatic amines:

aniline naphthylamine The following reactions with lithium or sodium cyanoborohydrides resulted in greater than 80% yield unless otherwise indicated:

' renaimr OET PliC=NMe CIiaNHMe OET PhCH=NCHzCH3 pncmwrcmon, Yield 65% P11c ET =N01-ncinc1n PhCIIZNIICIiZCIIZCIIQCIIiQ Yield 95% Thiamine dihydrothiamine or tetrahydrotlliamin Representative reductive aminations with lithium or sodium cyanoborohydride in methanol at C. are given in the following table.

A solution of (0.4 cc., 3. 9 m mole),

n-propylarnine (l .7cc,- 20m mole, and NaBH CN (65mg, 1.0m mole in 10 ml of MeOH was treated with 1 ml of ca. 4M. HCl/MeOH and stirred 90 hr. at 25. The methanol was evaporated at reduced pressure and the residue dissolved in 5m] 1N NaOH and extracted with 4+5 ml of ether. The combined ether extracts were extracted with 4+5 ml 1N HCl. The HCl extracts were made basic with 6N NaOH and back-extracted with 4+5 ml ether. The extracts were dried (MgS0 and evaporated to give 395 mg. of basic product. Glpc analysis showed 78% s -Nnr r 22 percent of another amine, probably s )NP1-- 2.e

7 moles product/ mole NaBHQC N used.

Synthesis of N-cyclohexyl-N-propyl amine 2 grams cyclohexanone (ZOmM), 6 grams n-propyl amine (lOOmM), mM HCl/MeOH were added to 35 ml absolute methanol in a 125 Erlenmeyer flask at room temperature. To this mixture was added 3.0 grams NaBH CN.C H O (20 mM, mM, hydride) and the mixture allowed to stand for 3 days at room temperature (flask stoppered with a cork). The methanolic solution was made strongly basic with 20 percent NaOH (-50 ml) and extracted with 5 X 20 ml ether. The ether was washed with 4 X 15 ml 2N HCl and the washings combined. The acid water layer was washed with 4 X 15 ml ether and then made strongly basic with solid KOH (cooling in ice bath necessary). The basic solution was extracted with 5 X 20 ml ether, the ether layers combined and washed with 4 X 20 ml saturated salt solution, and the ether dried over MgSO The so]- Yield Time Compound Amine (hrs.) Product Anal. Isolated NH3 36 63 4B /-=O -NH2 PhCHO CIIQCI'IZCIIQNIIL' 72 PhCHQNHET 91 Cyclohexanoncu (JIISCIIQCIIZNI'I! 84 N-propylcyclohexylamine 81 Cyclododecanone CIIQNI'ICI'IZ N,N-dimethylcyclododecylamine 71 66 PINHz Sodium phenylpymvate. NH; 36 (Ll-phenylalanine 4U 41 Synthesis of Alanine 110 mg sodium pyruvate (lmM), 500 mg NH Br (5 mM) and 151 mg NaBH CN C H, O were dissolved in 15 m1 absolute MeOl-l and allowed to stand at room temperature for 3 days. At the end of this time concen trated (6N) HCl was added to hydrolyze the hydride. The solvent and excess HCl were removed on a rotovac and the residue dissolved in H 0 and placed on a Dowex-SO ion-exchange resin in the acid form. The resin was washed with distilled water (2 liters) and the amino acid removed from the column with excess 1.5N ammonia. The ammonia solution was taken to dryness on a roto-vac and the residue dissolved in water. This solution was compared on TLC. cellulose with an authentic sample of alanine (BuOH, HOAc, H O 4:1:1). There was found to be only one ninhydrin positive spot with correspondence to alanine. Quantitative ninhydrin showed the yield to be 47 percent in this reaction.

Synthesis of Other Compounds SYNTHESIS OF OTHER COMPOUNDS Amines synthesized with LiBllzCN and NaBllrC-N Percent Analytical Isolated yield yield cyclohexanone 2-norbornan0ne H A q lnflvq i V t-yt-lnhvplnnom- 4... o g NH: arts 43 cyclooctauone E j J cyelododccanonc ucutuplwnom:

dibvnzyl kelonv nary i phenyl isopropyl ketone p i on tor SYNTHESIS OF OTHER COMPOUNDS-Continued lol'cvnl Analylicul Isolated yield yield 5)... (I) 1TH]? 54 3-acelyl pyridine Secondary amines :0 /H\CII 3 cumnycr 11 I o N-Clh 1: 0 llNCll;l no 71 H A Q 0mNn3+c1 iiN-Ciia m 90.5

3A-dimethoxybenzaldehydc SYNTHESIS OF OTHER COMlOUNDS-Continuo(l Percent Analytical Isolated yield yield 'lorliary amines synthesized with LiBlh CN and NaBIhCN nun-mu DMA" =0 -N(CH3)2 :0 N(CHJ)2 7 DMA* I 7 -nouanone SYNTHESIS OF OTHER COMlOUNDSContinued P orcent Analytical Isolated yield yield IQ l 0= (CHJ)2N@ cholestauonc h/Y DMA 0 N(CH )1 W V 4,4-dimethyl-2'peutauonu V Amines with NaB H3CNC H O2 NH- =Q NCH:CH2CH1 Amino acids from LiBHaCN 36.. O NIH u t 52 COz-Na NI-I +Cl- CO sodium pyruvale 37.. /COz-Na+ NHi Ck CO2- 49 O NH3+ sodium phenylpyi'uvate 38,. 00011 000- i as NIIH'CI C O OH CO OH :Z-kotoglularic acid 39" COOll GOO" =o NH +Cl' z-Nnr C O OH 0 O 011 .Z-ketosucciuic acid Amino acids from N8BH3CNC4H5O2 40.. O NH3+ 47 CI-I:J. lCOO"N8- NH 'Br- CHa- CO0- sodium pymvate Dimethylamine.

The numerous examples of the reaction of the invenl9 and 29 on page 8 (alkoxy substituted aryl); reaction tion indicate that the sole requirement of the com- 60 number 27 on page 8 (phenyl substituted alkyl); and pound being converted to an amine is that it contain an reactions numbers 38 and 39 on page 9 (carboxyl subimminium group. These examples indicate that substitstituted alkyl).

uents on the organic moieties R R R and R do not This application is a continuation of our co-pending affect the operativeness of the reduction reaction. In application Ser. No. 855,736 filed Sept. 5, 1958, now this connection attention is called to the reaction given 65 abandoned.

on page 5. line 10 (sodium phenyl pyruvate) and page We claim:

9, reaction number 37; reactions numbers 8 and 17 on 1. The method which comprises contacting a compage 7 (phenyl substituted alkyl); reactions numbers pound represented by the structural formula forms R-z forms a carbon ring, said compound being soluble in the selected solvent.

2. The method which comprises contacting a compound represented by the structural formula C=N-R2 with a substantially equivalent amount ofa cyanoborohydride selected from the group consisting of lithium, sodium, potassium and quaternary ammonium cyanoborohydrides and their corresponding deuterides and tritides and mixtures thereof in a solvent selected from 3 the group consisting of water, tetrahydrofuran, methanol, ethanol, diethyl ether and mixtures thereof having a pH between about 2 to 12 for a period of time sufficient to convert the imine group to an imminium group and convert the imminium group to an amine group, R, R and R being selected from the group consisting of H, alkyl, aryl, cycloalkyl, and cycloalkenyl groups,

C forms forms a carbon ring, said compound being soluble in the selected solvent.

3. The method which comprises contacting a compound represented by the structural formula \C=NR2 14 sisting of H, alkyl, R, aryl, cycloalkyl, and cycloalkenyl groups,

C forms ill (1:0 and with a substantially equivalent amount ofa cyanoborohydride selected from the group consisting of lithium, sodium, potassium and quaternary ammonium cyanoborohydrides and their corresponding deuterides and tritides and mixtures thereof in a solvent selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, diethyl ether and mixtures thereof having a pH between about 2 and 12, said solvent also containing a nitrogen compound selected from the group consisting of ammonia, primary alkyl and aryl amines and secondary alkyl amines, said contacting continuing for a period sufficient to convert the selected first compound to a compound containing an imminium group and convert the imminium group to an amine group, R and R representing a group selected from the group consisting of alkyl, R representing a group selected from the group consisting of alkyl, aryl, cycloalkyl, and cycloalkenyl groups,

(3 forms a forms a carbon ring said first compound being soluble in the selected solvent.

5. The method as claimed by claim 1 wherein the pH is between about 5 and 7.

6. The method as claimed by claim 2 wherein the pH is between about 5 and 7.

7. The method as claimed by claim 3 wherein the pH is between about 5 and 7.

8. The method as claimed by claim 1 wherein the pH is between about 7 and 9.

9. The method as claimed by claim 5 wherein the cyanoborohydride is sodium cyanoborohydride.

10. The method as claimed by claim 6 wherein the cyanoborohydride is sodium cyanoborohydride.

11. The method as claimed by claim 7 wherein the cyanoborohydride is sodium cyanoborohydride.

12. The method as claimed by claim 8 wherein the cyanoborohydride is sodium cyanoborohydride,

13. The method of claim 1 wherein R R R and R, are H or alkyl.

14. The method of claim 2 wherein R, R, and R are H or alkyl.

15. The method of claim 3 wherein R and R are H or alkyl.

16. The method of claim 4 wherein R and R, are H or alkyl. 

1. THE METHOD WHICH COMPRISES CONTACTING A COMPOUND REPRESENTED BY THE STRUCTURAL FORMULA
 2. The method which comprises contacting a compound represented by the structural formula
 3. The method which comprises contacting a compound represented by the structural formula
 4. The method which comprises contacting a first compound selected from those represented by the structural formula consisting of
 5. The method as claimed by claim 1 wherein the pH is between about 5 and
 7. 6. The method as claimed by claim 2 wherein the pH is between about 5 and
 7. 7. The method as claimed by claim 3 wherein the pH is between about 5 and
 7. 8. The method as claimed by claim 1 wherein the pH is between about 7 and
 9. 9. The method as claimed by claim 5 wherein the cyanoborohydride is sodium cyanoborohydride.
 10. The method as claimed by claim 6 wherein the cyanoborohydride is sodium cyanoborohydride.
 11. The method as claimed by claim 7 wherein the cyanoborohydride is sodium cyanoborohydride.
 12. The method as claimed by claim 8 wherein the cyanoborohydride is sodium cyanoborohydride.
 13. The method of claim 1 wherein R1, R2, R3 and R4 are H or alkyl.
 14. The method of claim 2 wherein R, R1 and R2 are H or alkyl.
 15. The method of claim 3 wherein R1 and R2 are H or alkyl.
 16. The method of claim 4 wherein R and R1 are H or alkyl. 